DIHYDROINDOLINONE DERIVATIVES

• US 20110275671A1
• Filed: 05/25/2009
• Published: 11/10/2011
• Est. Priority Date: 05/23/2008
• Status: Active Grant

• Current Assignee: Chia Tai Tianqing Pharmaceutical Group Co. Ltd. (SINO Biopharmaceutical Limited)
• Original Assignee: Shanghai Institute of Pharmaceutical Industry (China National Pharmaceutical Group Co., Ltd.)
• Inventors: Song, Wei, Yuan, Zhedong, Zhu, Xueyan, Fu, Hui, Zhang, Xiaomin, Xu, Hongjiang, Wang, Hubo
• Granted Patent: US 8,829,039 B2
• Time in Patent Office: Days
• US Class Current: 514/323
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

Abstract

Disclosed are dihydroindolone compounds which can modulate the activity of protein tyrosine kinases, a method for preparing the same, and pharmaceutical compositions comprising the same. Also disclosed are use of such compounds and pharmaceutical compositions thereof in the treatment and/or prophylaxis of protein tyrosine kinase associated diseases in an organism, particularly in the treatment and/or prophylaxis of tumors and fibroblast proliferation associated diseases.

Claims

1. A compound of formula I or a salt thereof, preferably a pharmaceutically acceptable salt thereof:

2. The compound or salt thereof of claim 1, wherein the optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocycloalkyl in R⁶ are each independently unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, aralkyl, amino, monoalkyl amino and dialkyl amino.

3. The compound or salt thereof of any one of claims 1-2, wherein R¹, R³ and R⁴ are each independently selected from the group consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy and aryl;

R² is selected from the group consisting of hydrogen, C₁-C₄ alkyl, halogen and cyano;

R⁵, R⁷ and R¹⁷ are each independently selected from the group consisting of hydrogen and C₁-C₄ alkyl;

R⁶ is selected from the group consisting of amino, monoalkyl amino, dialkyl amino, and aryl and heterocycloalkyl unsubstituted or substituted with a substituent selected from the group consisting of C₁-C₁ alkyl, aralkyl, amino, monoalkyl amino and dialkyl amino;

R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, C₁-C₄ alkyl, hydroxy and C₁-C₄ alkoxy; and

R¹⁵ and R¹⁶ are each independently selected from the group consisting of hydrogen and C₁-C₄ alkyl.

4. The compound or salt thereof of any one of claims 1-3, wherein R¹, R³ and R⁴ are each independently selected from the group consisting of hydrogen and C₁-C₄ alkyl;

R² is halogen;

R⁵, R⁷ and R¹⁷ are each independently selected from the group consisting of hydrogen and methyl;

R⁶ is selected from the group consisting of amino, monoalkyl amino, dialkyl amino, and phenyl and 5- or 6-membered heterocycloalkyl unsubstituted or substituted with a substituent selected from the group consisting of C₁-C₄ alkyl, aralkyl, amino, monoalkyl amino and dialkyl amino;

R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and C₁-C₄ alkyl; and

R¹⁵ and R¹⁶ are each independently C₁-C₄ alkyl.

5. The compound or salt thereof of claim 1, which is selected from a compound of formula II or a salt thereof:

6. The compound or salt thereof of claim 5, wherein R⁶ is selected from the group consisting of amino, monoalkyl amino, dialkyl amino, and aryl and heterocycloalkyl unsubstituted or substituted with a substituent selected from the group consisting of C₁-C₄ alkyl, aralkyl, amino, monoalkyl amino and dialkyl amino;

R⁸ and R⁹ are each independently selected from the group consisting of hydrogen, C₁-C₄ alkyl, hydroxy and C₁-C₄ alkoxy;

n1, n2 and n3 are each independently an integer from 0 to 2, and m is an integer from 0 to 1.

7. The compound or salt thereof of any one of claims 5-6, wherein R⁶ is selected from the group consisting of amino, monoalkyl amino, dialkyl amino, and phenyl or 5- or 6-membered heterocycloalkyl unsubstituted or substituted with a substituent selected from the group consisting of C₁-C₄ alkyl, aralkyl, amino, monoalkyl amino and dialkyl amino;

R⁸ and R⁹ are each independently selected from the group consisting of hydrogen and C₁-C₄ alkyl;

n1, n2 and n3 are each independently an integer from 0 to 2, and m is an integer from 0 to 1.

8. The compound or salt thereof of claim 1 or 5, which is selected from the following compounds or salts thereof:

9. A method for preparing the compound of any one of claims 1-4, comprising reacting an intermediate of formula III with an intermediate of formula IV:

10. A method for preparing the compound of any one of claims 5-7, comprising reacting an intermediate of formula V with an intermediate of formula VI:

11. A pharmaceutical composition comprising the compound or salt thereof of any one of claims 1-8 and one or more pharmaceutically acceptable carriers, excipients and/or vehicles.

12. A method for treating or preventing protein tyrosine kinases associated diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt thereof of any one of claims 1-8, or the pharmaceutical composition of claim 11.

13. The method of claim 12, wherein the protein tyrosine kinases associated diseases are tumors.

14. The method of claim 13, wherein the tumors include cervical carcinoma, liver cancer, lung cancer, gastric cancer, breast cancer, bladder cancer, head and neck cancer, ovarian cancer, prostate cancer, colorectal cancer, genitourinary tract cancer, melanoma, squamous cell carcinoma, astrocyte cancer, kaposi sarcoma, spongioblast cancer, preferably cervical carcinoma, liver cancer, lung cancer, gastric cancer, and breast cancer.

15. A method for treating or preventing fibroblast proliferation associated diseases, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt thereof of any one of claims 1-8 or the pharmaceutical composition of claim 11.

16. The method of claim 15, wherein the fibroblast proliferation associated diseases include pulmonary fibrosis, hepatic fibrosis, chronic pancreatitis, scleroderma, renal glomerular fibrosis, and multiple organ fibrosis supervened with radiochemotherapy and tissue transplantation.

17. A method for treating or preventing tumors, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt thereof of any one of claims 1-8 or the pharmaceutical composition of claim 11.

18. The method of claim 17, wherein the tumors include cervical carcinoma, liver cancer, lung cancer, gastric cancer, breast cancer, bladder cancer, head and neck cancer, ovarian cancer, prostate cancer, colorectal cancer, genitourinary tract cancer, melanoma, squamous cell carcinoma, astrocytes cancer, Kaposi sarcoma, and spongioblast cancer, preferably cervical carcinoma, liver cancer, lung cancer, gastric cancer, and breast cancer.